MAD1L1 and MAD2L1 genes variants in spontaneous miscarriage with aneuploidy

Aneuploidy accounts for over 57% of spontaneous abortions and occurs even in women of young reproductive age. Despite its major role in pregnancy loss, the genetic basis of fetal aneuploidy remains poorly characterized. This study evaluated the association of MAD1L1 and MAD2L1, two key spindle assembly checkpoint genes, with fetal aneuploidy in women younger than 36 years. Forty aborted fetuses with approved aneuploidy using array comparative genomic hybridization were enrolled in genotyping. The rs121908981 and rs121908982 pathogenic single nucleotide variants (SNVs) of exons 4 and 18 of MAD1L1 and all exons of MAD2L1 were studied in aneuploid fetuses using Sanger sequencing. Identified variants were classified based on ACMG guideline and their frequencies were compared with ethnically matched Iranome database. The effect of SNVs was predicted using the PredictSNP Webtool and Mobidetails database. No targeted pathogenic SNVs were identified in MAD1L1; however, nine other SNVs were detected. Among these, the rare Iranome variants rs1639921 and rs1481591257 were observed in the homozygous state in four and one POCs, respectively, and showed significantly different frequencies compared with Iranome (P < 0.005). The frequency of the deleterious MAD2L1 variant rs903147 did not differ from Iranome, although 15 POCs were homozygous for this variant. In addition, a novel 60-bp deletion in intron 4 of MAD1L1 was identified for the first time. Although more frequent in POCs, its frequency did not differ significantly from that in karyotypically normal controls. Collectively, the rare variants rs1639921 and rs1481591257 may be associated with aneuploidy in POCs.